This is a new grant application for the University of California, San Francisco; however, it is a continuation of grant AM-18349-05, an award to the University of Texas Health Science Center at San Antonio, under the direction of Ralph S. Goldsmith, MD. Dr. Goldsmith is moving from the University of Texas to the University of California, San Francisco, and will assume the position of Chief of Staff at the San Francisco Veterans Administration Medical Center. The research objectives will remain essentially the same, i.e., we will continue our studies in normal volunteers and in patients with a variety of diseases that have been characterized by vitamin D 'resistance' or 'sensitivity' such as cirrhosis, malabsorption, osteoporosis, sarcoidosis, etc. The data obtained by this research, using methods outlined, should provide a rational basis for the therapeutic uses of vitamin D and its metabolites. Because this application requests support for the sixth year of this project, the plans and objectives outlined are predicted on the progress and results obtained during the first five (5) years. A summary of that progress is attached as Addendum A. During the -06 year we propose: to continue clinical studies with special emphasis on those situations in which we predict possible dissociation between serum concentrations of vitamin D metabolites and their rates of synthesis; to investigate in detail the relationship between renal function and serum concentration of 1,25(OH)2D3. One aspect of this investigation will be administration of relatively large amounts of precursor 25(OH)D3 to determine if it is possible to induce increased activity of the 1 alpha-hydroxylase; to continue collaboration with Dr. Norman Bell to compare kinetics of 1,25(OH)2D3 as assessed by administration of 3H-labelled tracer 1,25(OH)2D3 and non-tracer, non-labelled 1,25(OH)2D3 in the same subjects; to proceed with collaborative studies with Dr. Rowe of the Department of Pediatrics at the University of Connecticut.